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2.
Molecules ; 24(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31454880

RESUMO

The early asymptomatic stage of glomerular injury is a diagnostic challenge in the course of renal and extra-renal disease, e.g., heart insufficiency. It was found that podocin, a podocyte-specific protein present in the urine, may serve as a biomarker in the diagnosis of glomerular disease in humans and animals including glomerulonephritis, glomerulosclerosis, amyloidosis, or nephropathy. Therefore, there is a need of development of the sensitive and straightforward method of urinary podocin identification. In this work, we report our extended research under the glomerular injury investigation in dogs by application of clinical examination and LC-MS-MRM method in the identification of canine podocin in urine samples. The LC-MS-MRM method is based on the identification of podocin tryptic peptide with the 218H-AAEILAATPAAVQLR-OH232 sequence. The model peptide was characterized by the highest ionization efficiency of all the proposed model podocin tryptic peptides in a canine urine sediment according to the LC-MS/MS analysis. The obtained results revealed the presence of the model peptide in 40.9% of dogs with MMVD (active glomerular injury secondary to heart disease = cardiorenal syndrome-CRS) and 33.3% dogs with chronic kidney disease. The potential applicability of the developed methodology in the analysis of podocin in canine urine sediments was confirmed.


Assuntos
Síndrome Cardiorrenal/veterinária , Doenças do Cão/diagnóstico , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteínas de Membrana/química , Peptídeos/urina , Insuficiência Renal Crônica/veterinária , Animais , Biomarcadores/urina , Síndrome Cardiorrenal/diagnóstico , Síndrome Cardiorrenal/urina , Cromatografia Líquida , Doenças do Cão/urina , Cães , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/urina , Masculino , Proteínas de Membrana/urina , Podócitos/citologia , Podócitos/metabolismo , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/urina , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
3.
Dis Markers ; 2019: 5432453, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354889

RESUMO

Background: Alterations in DNA methylation may be involved in disease progression in patients with chronic kidney disease (CKD). Recent studies have suggested that 5-methyl-2'-deoxycytidine (5MedC) may be a marker of hypermethylation of DNA. Currently, there is no information available regarding the urine levels of 5MedC and its association with the progression of CKD. Method: We examined the urine levels of 5MedC in spot urine samples from 308 patients with CKD (median age: 56 years, male: 53.2%, and glomerulonephritis: 51.0%) using a competitive enzyme-linked immunosorbent assay and investigated the relationships among urine 5MedC, urine albumin, urine α1-microglobulin (α1MG), and the laboratory parameters associated with CKD. The patients were followed for three years to evaluate renal endpoints in a prospective manner. Results: The urine 5MedC level was significantly increased in the later stages of CKD compared to the early to middle stages of CKD. In multiple logistic regression models, urine 5MedC was significantly associated with the prediction of later CKD stages. Urine 5MedC (median value, 65.9 µmol/gCr) was significantly able to predict a 30% decline in the estimated GFR or a development of end-stage renal disease when combined with macroalbuminuria or an increased level of urine α1MG (median value, 5.7 mg/gCr). Conclusion: The present data demonstrate that the urine 5MedC level is associated with a reduced renal function and can serve as a novel and potent biomarker for predicting the renal outcome in CKD patients. Further studies will be necessary to elucidate the role of urine DNA methylation in the progression of CKD.


Assuntos
Desoxicitidina Monofosfato/análogos & derivados , Insuficiência Renal Crônica/urina , Adulto , Idoso , Biomarcadores/urina , Metilação de DNA , Desoxicitidina Monofosfato/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia
4.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31356184

RESUMO

Dysfunction of heart leads inevitable to the dysfunction of kidney which is termed as the cardiorenal syndrome (CRS). Previous studies have confirmed existence of CRS in dogs with degenerative mitral valve disease (DMVD). The goal of the study was to assess the usefulness of commercial test to measure podocyturia in dogs and test the urine podocine/creatinine ratio (UPoC) as an early marker of kidney injury. Urine podocine/creatinine ratio was calculated because numbers of podocytes is dependent on the urine concentration. Fifty dogs was divided into three groups: fifteen healthy (control group), twenty nine with DMVD class C-chronic according to ACVIM (heart group) and six with chronic kidney disease (kidney group). Each dog underwent a clinical examination: electrocardiography, echocardiography, chest radiograph, abdominal ultrasound, blood haematological and biochemical analysis including symmetric dimethylarginine (SDMA) and cystatin C (Cyst C), routine urine analysis and analysis of podocytes using an ELISA test. UPoC was calculated. Mean value ± standard deviation for UPoC was respectively 9.7 ± 4.8 x 10-10 for control group, 49.0 ± 80.0 x 10-10 for heart group, 33.7 ± 18.0 x 10-10 for kidney group. The UPoC in the heart and kidney group was significantly higher than in the control group (P < 0.0001, sensivity 0.83, specyfity 0.20). Commercial ELISA tests may be used to assess podocyturia in dogs. An UPoC increase exceeding 12.93 x 10-10 indicates glomerular damage in DMVD dogs. Based on UPoC, 79.3% of dogs with C-chronic stage of DMVD developed CRS.


Assuntos
Biomarcadores/urina , Síndrome Cardiorrenal/urina , Creatinina/urina , Doenças das Valvas Cardíacas/urina , Peptídeos e Proteínas de Sinalização Intracelular/urina , Proteínas de Membrana/urina , Animais , Cães , Feminino , Masculino , Valva Mitral/metabolismo , Insuficiência Renal Crônica/urina
5.
Vet J ; 249: 73-79, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31239169

RESUMO

Chronic kidney disease (CKD) is clinically important in canine medicine. Current diagnostic tools lack sensitivity for detection of subclinical CKD. The aim of the present study was to evaluate urinary peptidome analysis for diagnosis of CKD in dogs. Capillary electrophoresis coupled to mass spectrometry analysis demonstrated presence of approximately 5400 peptides in dog urine. Comparison of urinary peptide abundance of dogs with and without CKD led to the identification of 133 differentially excreted peptides (adjusted P for each peptide <0.05). Sequence information was obtained for 35 of these peptides. This 35 peptide subset and the total group of 133 peptides were used to construct two predictive models of CKD which were subsequently validated by researchers masked to results in an independent cohort of 20 dogs. Both models diagnosed CKD with an area under the receiver operating characteristic (ROC) curve of 0.88 (95% confidence intervals [CI], 0.72-1.0). Most differentially excreted peptides represented fragments of collagen I, indicating possible association with fibrotic processes in CKD (similar to the equivalent human urinary peptide CKD model, CKD273). This first study of the urinary peptidome in dogs identified peptides that were associated with presence of CKD. Future studies are needed to validate the utility of this model for diagnosis and prediction of progression of canine CKD in a clinical setting.


Assuntos
Doenças do Cão/urina , Peptídeos/urina , Insuficiência Renal Crônica/veterinária , Animais , Biomarcadores/urina , Estudos de Coortes , Doenças do Cão/diagnóstico , Cães , Eletroforese Capilar/veterinária , Feminino , Masculino , Espectrometria de Massas/veterinária , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/urina , Análise de Sequência de Proteína , Urinálise/métodos , Urinálise/veterinária
6.
Ren Fail ; 41(1): 540-546, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31234687

RESUMO

Low serum 25 hydroxyvitamin D (25 OH D) is common among chronic kidney disease (CKD) patients. This cross-sectional study is looking for the different factors associated with serum 25 OH D among pre-dialysis CKD. 1624 adult stage 3-5 CKD patients were studied beside 200 normal control subjects. All candidates were tested for body mass index (BMI), estimated glomerular filtration rate (eGFR), calcium (Ca), phosphorus (P), parathormone (PTH), 25 OH D, albumin, and uric acid (UA), and urine albumin/creatinine ratio (ACR). Multivariate linear regression analysis was done to determine predictors of 25 OH D. 98.6% of CKD patients have inadequate level of 25 OH D vs 48% of normal subjects. Serum 25 OH D was significantly lower in CKD patients (mean ± S.D = 16.54 ± 5.8 vs 37.79 ± 3.58 ng/mL for CKD vs control group respectively, p < .001). Serum level of 25 OH D has significant positive correlation with Ca (r = 0.337, p < .001), and significant negative correlation with P, PTH, UA, and ACR (r = -0.440, -0. 679, -0.724, and -0.781respectively, p < .001 in all). The independent predictors of 25 OH D were Ca, P, UA, PTH, and ACR (R square = 0.7, ß = -0.087, -0.226, -0.313, -0.253, and -0.33 respectively, p < .001 in all). In conclusion, pre-dialysis CKD patients frequently suffer low 25 OH D. Among the different abnormalities related to CKD, urine albumin excretion rate and UA are the most important predictors of 25 OH D in these patients.


Assuntos
Albuminúria/urina , Insuficiência Renal Crônica/complicações , Ácido Úrico/sangue , Deficiência de Vitamina D/diagnóstico , Vitamina D/análogos & derivados , Adolescente , Adulto , Albuminas/análise , Albuminúria/sangue , Albuminúria/etiologia , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/urina , Vitamina D/sangue , Deficiência de Vitamina D/etiologia , Adulto Jovem
7.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
8.
Talanta ; 201: 211-216, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122413

RESUMO

Specific monitoring of cystatin C (CysC) levels in biological fluids is critical for diagnosis, treatment and mechanistic understanding of a spectrum of diseases, particularly chronic kidney disease (CKD). Despite evidences that CysC correlates with the high risk and/or progression of CKD, its use in clinical practice is still scarce. In this context, we report the development of a simple and sensitive immunosensor for the detection of CysC. The biosensor combines the technology of cost-effective screen-printed electrodes with the high specificity of a sandwich immunoassay. Optimized conditions showed that the sensor operates in a linear range between 10 and 100 ng mL-1, with a detection limit and a sensitivity of 6.0 ng mL-1 and 6.4 ±â€¯0.3 µA ng mL-1 cm-2, respectively. Moreover, the sensor provided precise results (RSD ≤ 6.2%) and the quantification of CysC in CKD serum samples revealed to be in agreement with the values obtained by a particle-enhanced nephelometric immunoassay. In this light, the proposed immunosensor qualifies for clinical application, constituting a step forward in the development of fast, sensitive and cost-effective diagnostic tools that can improve the current medical care settings of CKD patients.


Assuntos
Cistatina C/urina , Técnicas Eletroquímicas/métodos , Imunoensaio/métodos , Animais , Anticorpos Monoclonais Murinos/imunologia , Biomarcadores/urina , Carbono/química , Cistatina C/imunologia , Técnicas Eletroquímicas/instrumentação , Eletrodos , Ouro/química , Humanos , Limite de Detecção , Nanopartículas Metálicas/química , Camundongos , Insuficiência Renal Crônica/urina
9.
Medicine (Baltimore) ; 98(21): e15808, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31124979

RESUMO

Data on risk factors predicting rapid progression to end-stage renal disease (ESRD) or short-term kidney function decline (i.e., within 1 year) in chronic kidney disease (CKD) are rare but urgently needed to plan treatment. This study describes the association and predictive value of urinary uromodulin (uUMOD) for rapid progression of CKD.We assessed uUMOD, demographic/treatment parameters, estimated glomerular filtration rate (eGFR), and proteinuria in 230 CKD patients stage I-V. ESRD and 25% decline of eGFR was documented at the end of follow-up period and used as a composite endpoint. Association between logarithmic uUMOD and eGFR/proteinuria was calculated using linear regression analysis, adjusting for age, gender, and body mass index. We performed multivariable Cox proportional hazard regression analysis to evaluate the association of uUMOD with the composite endpoint. Therefore, patients were categorized into quartiles. The predictive value of uUMOD for the above outcomes was assessed using receiver-operating characteristic (ROC) curve analysis.Follow-up was 57.3 ±â€Š18.7 weeks, baseline age was 60 (18;92) years, and eGFR was 38 (6;156) mL/min/1.73 m. Forty-seven (20.4%) patients reached the composite endpoint. uUMOD concentrations were directly associated with eGFR and inversely associated with proteinuria (ß = 0.554 and ß = -0.429, P < .001). In multivariable Cox regression analysis, the first 2 quartiles of uUMOD concentrations had a hazard ratio (HR) of 3.589 [95% confidence interval (95% CI) 1.002-12.992] and 5.409 (95% CI 1.444-20.269), respectively, in comparison to patients of the highest quartile (≥11.45 µg/mL) for the composite endpoint. In ROC-analysis, uUMOD predicted the composite endpoint with good sensitivity (74.6%) and specificity (76.6%) at an optimal cut-off at 3.5 µg/mL and area under the curve of 0.786 (95% CI 0.712-0.860, P < .001).uUMOD was independently associated with ESRD/rapid loss of eGFR. It might serve as a robust predictor of rapid kidney function decline and help to better schedule arrangements for future treatment.


Assuntos
Falência Renal Crônica/etiologia , Testes de Função Renal/estatística & dados numéricos , Proteinúria/etiologia , Insuficiência Renal Crônica/urina , Uromodulina/urina , Adulto , Idoso , Área Sob a Curva , Estudos de Coortes , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/fisiopatologia , Testes de Função Renal/métodos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Curva ROC , Insuficiência Renal Crônica/complicações , Fatores de Risco
10.
J Trace Elem Med Biol ; 54: 206-213, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31109613

RESUMO

Chronic kidney disease of uncertain etiology (CKDu) in areas in and around Sri Lanka's North Central Province has been identified as a major non-communicable disease due to its high prevalence and the burden on the public health system. Controversial evidence relating to the etiology and risk factors of CKDu has been reported. The most debated is the role of trace elements such as Cd and As in the pathogenesis of CKDu. Urine and hair samples collected from CKDu patients and healthy controls were measured for the concentration of different elements including Cd and As. To assess the possible environmental exposures, drinking water and rice samples collected from the affected areas as well as unaffected areas in the country were analyzed. Transmission electronic microscopic analysis of renal biopsies from CKDu patients was also performed. Analysis of drinking water and rice samples indicated that the levels of all minerals and trace elements analyzed including Cd and As were within the levels recommended by World Health Organization and Sri Lanka drinking water guidelines and did not suggest any form of contamination. Analysis of biological samples, including urine, hair and renal tissue, did not provide evidence to support Cd or As toxicity in CKDu patients. Overall, the observations of this integrated, comprehensive study, which included biological, environmental and pathological investigations, strongly support our previous reports on the absence of Cd and As toxicity in areas with high prevalence of CKDu. Further, these observations do not provide evidence on the involvement of Cd and As in pathogenesis of CKDu in Sri Lanka.


Assuntos
Água Potável/química , Minerais/análise , Oligoelementos/análise , Arsênico/análise , Cádmio/análise , Exposição Ambiental , Humanos , Oryza/química , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/urina , Sri Lanka
11.
Clin Exp Nephrol ; 23(9): 1109-1118, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31131423

RESUMO

BACKGROUND: A higher heart rate is one of the risk factors for heart failure and cardiovascular disease. Activation of the intrarenal renin-angiotensin system (RAS) plays an important role in the development of hypertension and renal damage. However, the association between heart rate and intrarenal RAS activation is unclear. METHODS: We investigated the relationship between heart rate and urinary angiotensinogen (U-AGT) excretion, a surrogate marker for intrarenal RAS activity, in ten subjects without chronic kidney disease (CKD) and 72 CKD patients who were not taking medications that influence heart rate and RAS blockers (age 50.0 ± 17.4 years, 27 men and 45 women, serum creatinine (sCr) 1.85 ± 2.71 mg/dL, blood pressure 120.5 ± 15.8/72.9 ± 10.1 mmHg, heart rate 67.3 ± 8.9 /min, urinary protein excretion 1.27 ± 2.63 g/day, and U-AGT excretion 747.4 ± 2714.6 µg/day). RESULTS: As heart rate is influenced by behavior and emotion, we divided it into daytime and nighttime. Heart rate had a significant positive association with sCr levels during daytime and nighttime in CKD patients but not in non-CKD subjects. Moreover, although heart rate was not associated with U-AGT excretion levels in non-CKD subjects, it was associated with U-AGT excretion levels during daytime (r = 0.23 and p = 0.047) and nighttime (r = 0.45 and p < 0.01) in CKD patients. Multiple linear regression analysis revealed that heart rate had a significant positive association with the U-AGT excretion levels during nighttime, but not daytime, after adjustments for age, sex, body mass index, and sCr (ß = 0.31 and p = 0.034). CONCLUSION: Heart rate is associated with U-AGT excretion levels, especially during the nighttime, in CKD patients.


Assuntos
Angiotensinogênio/urina , Ritmo Circadiano , Frequência Cardíaca , Rim/metabolismo , Insuficiência Renal Crônica/urina , Sistema Renina-Angiotensina , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Casos e Controles , Creatinina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Fatores de Tempo , Adulto Jovem
12.
Int J Mol Sci ; 20(8)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027235

RESUMO

Chronic kidney disease-mineral bone disorder (CKD-MBD), comprising mineral, hormonal, and bone metabolic imbalance, is a major CKD-related issue; it causes osteoporosis prevalence in CKD patients. Osteocyte-derived sclerostin inhibits the osteogenic Wnt/ß-catenin signaling pathway; its levels rise when kidney function declines. Exercise modulates the physiological functions of osteocytes, potentially altering sclerostin production. It may aid bone and mineral electrolyte homeostasis in CKD. Mild CKD was induced in rats by partial nephrectomy. They were divided into: sham (no CKD), CKD, and CKD + exercise (8 weeks of treadmill running) groups. Micro-CT scanning demonstrated that the CKD + exercise-group rats had a higher bone mineral density (BMD) of the spine and femoral metaphysis and higher femoral trabecular bone volume than the CKD-group rats. Bone formation rates were not significantly different. The CKD + exercise-group rats had lower serum sclerostin (157.1 ± 21.1 vs 309 ± 38.1 pg/mL, p < 0.05) and CTX-1 (bone resorption marker) levels. Immunohistochemistry revealed higher tibial ß-catenin concentrations in the CKD + exercise-group rats. Serum FGF-23, intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), calcium, and phosphate levels showed no significant differences between these groups. Thus, exercise improves BMD and bone microstructure in mild CKD by inhibiting sclerostin production, but does not alter serum minerals.


Assuntos
Proteínas Morfogenéticas Ósseas/biossíntese , Osteoporose/complicações , Osteoporose/prevenção & controle , Condicionamento Físico Animal , Insuficiência Renal Crônica/complicações , Animais , Biomarcadores/sangue , Biomarcadores/urina , Densidade Óssea , Proteínas Morfogenéticas Ósseas/sangue , Proteínas Morfogenéticas Ósseas/metabolismo , Reabsorção Óssea/sangue , Reabsorção Óssea/patologia , Reabsorção Óssea/fisiopatologia , Reabsorção Óssea/urina , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/patologia , Marcadores Genéticos , Rim/patologia , Rim/fisiopatologia , Masculino , Tamanho do Órgão , Osteócitos/metabolismo , Osteoporose/sangue , Osteoporose/urina , Ratos Sprague-Dawley , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/urina , Tíbia/patologia , beta Catenina/metabolismo
13.
Lancet ; 393(10184): 1937-1947, 2019 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-30995972

RESUMO

BACKGROUND: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. METHODS: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. FINDINGS: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4-2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49-0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85-2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75-1·59]; p=0·65). INTERPRETATION: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. FUNDING: AbbVie.


Assuntos
Atrasentana/administração & dosagem , Creatinina/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor de Endotelina A/administração & dosagem , Insuficiência Renal Crônica/prevenção & controle , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrasentana/uso terapêutico , Creatinina/urina , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/urina , Método Duplo-Cego , Antagonistas do Receptor de Endotelina A/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/urina , Albumina Sérica Humana/urina , Resultado do Tratamento , Adulto Jovem
14.
Clin Chim Acta ; 495: 239-250, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31009602

RESUMO

INTRODUCTION: Chronic kidney disease (CKD) is a silent disease. Most CKD patients are unaware of their condition during the early stages of the disease which poses a challenge for healthcare professionals to institute treatment or start prevention. The trouble with the diagnosis of CKD is that in most parts of the world, it is still diagnosed based on measurements of serum creatinine and corresponding calculations of eGFR. There are controversies with the current staging system, especially in the methodology to diagnose and prognosticate CKD. OBJECTIVE: The aim of this review is to examine studies that focused on the different types of samples which may serve as a good and promising biomarker for early diagnosis of CKD or to detect rapidly declining renal function among CKD patient. METHOD: The review of international literature was made on paper and electronic databases Nature, PubMed, Springer Link and Science Direct. The Scopus index was used to verify the scientific relevance of the papers. Publications were selected based on the inclusion and exclusion criteria. RESULT: 63 publications were found to be compatible with the study objectives. Several biomarkers of interest with different sample types were taken for comparison. CONCLUSION: Biomarkers from urine samples yield more significant outcome as compare to biomarkers from blood samples. But, validation and confirmation with a different type of study designed on a larger population is needed. More comparison studies on different types of samples are needed to further illuminate which biomarker is the better tool for the diagnosis and prognosis of CKD.


Assuntos
Biomarcadores/sangue , Biomarcadores/urina , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/urina , Taxa de Filtração Glomerular , Humanos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia
15.
Clin Exp Nephrol ; 23(8): 1013-1021, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30955187

RESUMO

BACKGROUND: Previously we found that kidney tissue and urinary exosomes from patients of diabetic kidney disease showed high levels of ceruloplasmin (CP). Because CP is an acute-phase protein of kidney origin, it could be an early marker of many other kidney diseases. To investigate this hypothesis, we first measured urine exosomal and kidney expression of CP in non-diabetic chronic kidney disease (CKD) patients (membranous nephropathy, focal segmental glomerulosclerosis, lupus nephritis and IgA nephropathy) followed by a longitudinal study in rat passive Heymann nephritis (PHN), a model of human membranous nephropathy. METHODS: Urinary exosomes were isolated from urine of patients (and rats) by differential centrifugation. The exosomal extracts were used for measuring CP using ELISA. Kidney expression of CP was evaluated by immune-staining biopsy tissues. Similar techniques were applied in rat PHN model (produced by injection of anti-gp600 antiserum) to analyze urine exosomal and kidney CP. RESULTS: Urine exosomal CP levels were 10-20 times higher in CKD patients than in controls; consistent with this we found high immune-reactive CP localized in tubules and collecting ducts of biopsies of CKD patients. In the PHN model urinary exosomal CP level was significantly higher prior to the onset of proteinuria. Early rise of urine exosomal CP, which preceded proteinuria, correlated with high immunoreactive CP found in rat kidneys at this time. CONCLUSION: We propose that urine exosomal CP, observed to increase prior to proteinuria, makes it a potential urinary biomarker to diagnose early kidney disease.


Assuntos
Ceruloplasmina/urina , Exossomos/enzimologia , Glomerulonefrite Membranosa/urina , Rim/enzimologia , Proteinúria/urina , Insuficiência Renal Crônica/urina , Adulto , Animais , Biomarcadores/urina , Estudos de Casos e Controles , Modelos Animais de Doenças , Diagnóstico Precoce , Exossomos/patologia , Feminino , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/enzimologia , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Proteinúria/diagnóstico , Proteinúria/enzimologia , Ratos Sprague-Dawley , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/enzimologia , Regulação para Cima
16.
Clin Exp Nephrol ; 23(7): 948-955, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30955189

RESUMO

BACKGROUND: Insulin resistance is one of the risks of chronic kidney disease (CKD). The triglyceride-glucose index (TyG index) has been suggested as a marker of moderate insulin resistance. We aimed to investigate the association between TyG index and incident CKD. METHODS: In this historical cohort study of 11,712 participants (6026 men and 5686 women), we investigated the impact of TyG index on incident CKD. CKD was defined as estimated GFR less than 60 mL/min/1.73 m2 and/or proteinuria detected by dipstick test in fasting morning urine. TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. Cox proportional hazard models were performed to investigate the impact of TyG index on incident CKD, adjusting for age, BMI categories, waist circumference, smoking status, exercise, logarithm of alcohol consumption, systolic blood pressure, serum albumin, hemoglobin A1c, hyperuricemia, low HDL-cholesterol concentration, high LDL-cholesterol concentration, CRP, creatinine, and gamma-glutamyltransferase. RESULTS: During the median 4.0-year follow-up duration for men and 3.7-year follow-up duration for women, 261 participants (120 men and 141 women) developed CKD. In Cox proportional hazard model, TyG index presented the significant risks for incident CKD in both men and women (men, hazard ratio 1.32, 95% confidence interval 1.02-1.70, p = 0.036, women, hazard ratio 1.50, 95% confidence interval 1.05-2.13, p = 0.024). CONCLUSION: This study revealed that TyG index can be a predictor of incident CKD.


Assuntos
Glicemia/metabolismo , Resistência à Insulina , Insuficiência Renal Crônica/epidemiologia , Triglicerídeos/sangue , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Humanos , Incidência , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteinúria/sangue , Proteinúria/epidemiologia , Proteinúria/urina , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/urina , Medição de Risco , Fatores de Risco , Fatores de Tempo
17.
Nefrología (Madrid) ; 39(2): 124-132, mar.-abr. 2019. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-181319

RESUMO

En esta revisión discutimos el valor diagnóstico de los parámetros urinarios en la enfermedad renal crónica avanzada y exponemos los conceptos clave que resumen las sugerencias del manuscrito. Volumen de orina: La cantidad de líquido ingerida puede ser un factor de riesgo de enfermedad renal crónica no establecido. Alcanzar una diuresis ≥ 2-3 l al día es una propuesta razonable, no aplicable al síndrome cardiorrenal y riesgo de retención hidrosalina. Naur_ determinación útil para vigilar la ingesta salina. Reducir la natriuresis < 120 mEq/d (≅ingesta sal ≤5 - 6g) es un objetivo razonable. Nitrógeno ureico urinario (NUU). Útil para estimar la ingesta proteica (ecuación de Maroni). Una ingesta proteica entre 48-72 g (0,8 - 0,9 g/kg/día según peso) ≅NUU 7-10 g/día aproximadamente. Carga ácida y potasio. La reducción de la carga ácida puede ser una estrategia adicional en el manejo nutricional de esta población. Puede estimarse de forma indirecta desde la encuesta dietética o midiendo la eliminación de NUU y Kur. Los límites en la recomendación no están establecidos; proponemos una liberación prudente de verduras y frutas. Fósforo: Existe estrecha asociación entre proteínas y fósforo, tanto en registro dietético como eliminación urinaria. El análisis combinado sugiere que para pacientes con FG<25 mil/min, una fosfaturia < 800mg/día, y con FG < 15 mil/min, una fosfaturia<600mg son objetivos razonables. Conclusión: Los parámetros urinarios proporcionan conocimiento sensible y de utilidad para la práctica clínica; aportan información de los hábitos dietéticos del paciente y de la adherencia a nuestras recomendaciones


This review discusses the diagnostic value of urinary parameters in the setting of advanced chronic kidney disease and we present the key concepts that summarise the suggestions of the manuscript. Urinary volume: The amount of fluid intake may be a non-established risk factor for CKD. For these patients, a urinary output ≥ 2-3 l/day is a reasonable proposal. This recommendation is not applicable to patients with cardiorenal syndrome or fluid overload risk. Naur:This determination is very useful to monitor salt intake. Reducing urinary Na < 120 mEq/day (≅salt intake ≤ 5-6 g) is a reasonable objective. Urinary urea nitrogen (UUN): This parameter is useful to estimate protein intake (Maroni BJ equation). A protein intake between 48-72 g (0.8-0.9 g/kg/day according to weight) is equivalent to UUN 7-10 g/day approximately. Acid load and potassium: Acid load reduction may be an additional strategy in the nutritional management of this population. It may be estimated indirectly from a diet survey or by measuring the elimination of UUN and Kur. The limits of this recommendation have not been established, but we propose a cautious and prudent diet of fruit and vegetables. Phosphorus: There is a significant positive correlation between phosphorus and protein, both in dietary records and urine elimination. Based on this information, we suggest a urinary P excretion < 800 mg/day or < 600 mg/day for patients with GFR < 25 ml/min or < 15 ml/min, respectivel


Assuntos
Humanos , Parâmetros , Insuficiência Renal Crônica/epidemiologia , Fatores de Risco , Urina/química , Insuficiência Renal Crônica/urina , Natriurese , Estado de Hidratação do Organismo , Concentração Osmolar
18.
JAMA Intern Med ; 179(4): 542-551, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30830167

RESUMO

Importance: Oxalate is a potentially toxic terminal metabolite that is eliminated primarily by the kidneys. Oxalate nephropathy is a well-known complication of rare genetic disorders and enteric hyperoxaluria, but oxalate has not been investigated as a potential contributor to more common forms of chronic kidney disease (CKD). Objective: To assess whether urinary oxalate excretion is a risk factor for more rapid progression of CKD toward kidney failure. Design, Setting, and Participants: This prospective cohort study assessed 3123 participants with stages 2 to 4 CKD who enrolled in the Chronic Renal Insufficiency Cohort study from June 1, 2003, to September 30, 2008. Data analysis was performed from October 24, 2017, to June 17, 2018. Exposures: Twenty-four-hour urinary oxalate excretion. Main Outcomes and Measures: A 50% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD). Results: This study included 3123 participants (mean [SD] age, 59.1 [10.6] years; 1414 [45.3%] female; 1423 [45.6%] white). Mean (SD) eGFR at the time of 24-hour urine collection was 42.9 (16.8) mL/min/1.73 m2. Median urinary excretion of oxalate was 18.6 mg/24 hours (interquartile range [IQR], 12.9-25.7 mg/24 hours) and was correlated inversely with eGFR (r = -0.13, P < .001) and positively with 24-hour proteinuria (r = 0.22, P < .001). During 22 318 person-years of follow-up, 752 individuals reached ESRD, and 940 individuals reached the composite end point of ESRD or 50% decline in eGFR (CKD progression). Higher oxalate excretion was independently associated with greater risks of both CKD progression and ESRD: compared with quintile 1 (oxalate excretion, <11.5 mg/24 hours) those in quintile 5 (oxalate excretion, ≥27.8 mg/24 hours) had a 33% higher risk of CKD progression (hazard ratio [HR], 1.33; 95% CI, 1.04-1.70) and a 45% higher risk of ESRD (HR, 1.45; 95% CI, 1.09-1.93). The association between oxalate excretion and CKD progression and ESRD was nonlinear and exhibited a threshold effect at quintiles 3 to 5 vs quintiles 1 and 2. Higher vs lower oxalate excretion (at the 40th percentile) was associated with a 32% higher risk of CKD progression (HR, 1.32; 95% CI, 1.13-1.53) and 37% higher risk of ESRD (HR, 1.37; 95% CI, 1.15-1.63). Results were similar when treating death as a competing event. Conclusions and Relevance: Higher 24-hour urinary oxalate excretion may be a risk factor for CKD progression and ESRD in individuals with CKD stages 2 to 4.


Assuntos
Taxa de Filtração Glomerular/fisiologia , Oxalatos/urina , Insuficiência Renal Crônica/urina , Adulto , Idoso , Biomarcadores/urina , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Fatores de Risco , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia , Adulto Jovem
19.
BMC Vet Res ; 15(1): 54, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744640

RESUMO

BACKGROUND: Chronic kidney disease (CKD) is one of the most common diseases occurring in cats. It is characterized by renal fibrosis, which is strongly correlated with impairment of renal function. Since renal biopsy is not performed routinely in clinical practice, the non-invasive method of ultrasonographic shear-wave elastography (SWE) was used to determine renal parenchymal stiffness. Currently, urinary procollagen type III amino-terminal propeptide (uPIIINP) is a renal fibrosis biomarker in humans. Moreover, PIIINP is increasingly applied for identification of fibrosis in various organs in animals. RESULTS: The Young's modulus (E) value on SWE, uPIIINP, and renal function were evaluated in 23 CKD cats and 25 healthy cats (HC). The renal cortical E values were significantly higher than those of the renal medulla in both groups (P < 0.001). The E values of the renal cortex and medulla were significantly higher in CKD cats than in HC (P < 0.001 and P < 0.01, respectively). The E values, especially of the cortex, showed a significant positive correlation with concentrations of plasma creatinine (P < 0.001), blood urea nitrogen (P < 0.05), while they had a negative correlation with urine specific gravity (P < 0.001) and urine osmolality per plasma osmolality ratio (P < 0.01). The uPIIINP to creatinine ratios (uPIIINP/Cr) were significantly higher in CKD cats than in HC (P < 0.01) and were highly correlated with renal cortical E values (P < 0.001). CONCLUSIONS: SWE might be an additively useful and non-invasive diagnostic imaging tool to evaluate renal parenchymal stiffness, which correlates with renal functional impairment in CKD cats. Moreover, the uPIIINP/Cr might be a promissing biomarker for adjunctive assessing the renal fibrosis in feline CKD.


Assuntos
Doenças do Gato/diagnóstico , Técnicas de Imagem por Elasticidade/veterinária , Fragmentos de Peptídeos/urina , Pró-Colágeno/urina , Insuficiência Renal Crônica/veterinária , Animais , Biomarcadores/urina , Estudos de Casos e Controles , Doenças do Gato/diagnóstico por imagem , Doenças do Gato/urina , Gatos , Estudos Transversais , Técnicas de Imagem por Elasticidade/métodos , Feminino , Rim/diagnóstico por imagem , Masculino , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/urina
20.
Cell Physiol Biochem ; 52(1): 27-39, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30790503

RESUMO

BACKGROUND/AIMS: SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD). METHODS: CKD was induced in rats by feeding them adenine (0.25%w/w for 35 days) and canagliflozin (10 or 25 mg/kg, by gavage) was given with or without adenine. Several conventional and novel plasma and urine biomarkers and tissues morphology were used to investigate the canagliflozin effect on kidney structure and function. RESULTS: Rats fed adenine showed the typical features of CKD that included elevation of blood pressure, decreased food intake and growth, increased water intake and urine output, decrease in creatinine clearance, and increase in urinary albumin/creatinine ratio, liver-type fatty acid binding protein, N-acetyl-beta-D-glucosaminidase, and plasma urea, creatinine, uric acid, calcium, indoxyl sulfate and phosphorus concentrations. Adenine also increased concentrations of several biomarkers of inflammation such as neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor alpha, clusterin, cystatin C and interleukin-1ß, and decreased some oxidative biomarkers in kidney homogenate, such as superoxide dismutase, catalase, glutathione reductase, total antioxidant activity, and also urinary 8-isoprostane and urinary 8-hydroxy-2-deoxy guanosine. Adenine significantly increased the renal protein content of Nrf2, caused renal tubular necrosis and fibrosis. Given alone, canagliflozin at the two doses used did not significantly alter any of the parameters mentioned above. When canagliflozin was given concomitantly with adenine, it significantly and dose - dependently ameliorated all the measured adenine - induced actions. CONCLUSION: Canagliflozin ameliorated adenine - induced CKD in rats, through reduction of several inflammatory and oxidative stress parameters, and other indices such as uremic toxins, and by antagonizing the increase in the renal content of the transcription factor Nrf2. The drug caused no overt or significant untoward effects, and its trial in patients with CKD may be warranted.


Assuntos
Adenina/efeitos adversos , Canagliflozina/farmacologia , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Adenina/farmacologia , Animais , Biomarcadores/urina , Ratos , Ratos Wistar , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/prevenção & controle , Insuficiência Renal Crônica/urina
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